Megakaryocytes and erythroid cells are thought to derive from a common progenitor during hematopoietic differentiation. Although a number of transcriptional regulators are important for this process, they do not explain the bipotential result. We have recently shown by gain- and loss-of-function studies, expression profiling, and molecular analyses that EKLF, a transcription factor whose role in erythroid gene regulation is well established, plays an unexpected directive role in erythroid and megakaryocyte lineage decisions prior to establishment of the red cell compartment. We thus propose to extend these studies by: (1) examining the effect of EKLF gain- and loss-of-function on the bipotential lineage decisions made by the megakaryocyte-erythroid progenitor;(2) determining the mechanism by which EKLF regulates megakaryocyte gene repression, following the predictions made by a cross-antagonistic intracellular model. PUBLIC HEALTH RELEVANCE These studies are relevant to delineating the intracellular mechanisms that regulate bipotential decisions during mammalian hematopoiesis and result in commitment to specific lineages. Consequently, they are relevant to clinical studies that depend on optimal expansion of progenitors for their use in medical applications. We have novel evidence that a particular transcription factor that we identified may play a critical role in progenitor/progeny decisions during a specific stage in hematopoiesis, and would like to determine how it accomplishes this.